CSR-1 RNAi pathway positively regulates histone expression in C. elegans.

Endogenous small interfering RNAs (endo-siRNAs) have been discovered in many organisms, including mammals. In C. elegans, depletion of germline-enriched endo-siRNAs found in complex with the CSR-1 Argonaute protein causes sterility and defects in chromosome segregation in early embryos. We discovered that knockdown of either csr-1, the RNA-dependent RNA polymerase (RdRP) ego-1, or the dicer-related helicase drh-3, leads to defects in histone mRNA processing, resulting in severe depletion of core histone proteins. The maturation of replication-dependent histone mRNAs, unlike that of other mRNAs, requires processing of their 3'UTRs through an endonucleolytic cleavage guided by the U7 snRNA, which is lacking in C. elegans. We found that CSR-1-bound antisense endo-siRNAs match histone mRNAs and mRNA precursors. Consistently, we demonstrate that CSR-1 directly binds to histone mRNA in an ego-1-dependent manner using biotinylated 2'-O-methyl RNA oligonucleotides. Moreover, we demonstrate that increasing the dosage of histone genes rescues the lethality associated with depletion of CSR-1 and EGO-1. These results support a positive and direct effect of RNAi on histone gene expression.

Unrecognized Celiac Disease in Children Presenting for Rheumatology Evaluation.

BACKGROUND AND OBJECTIVES: Current clinical guidelines do not consider patients with rheumatic conditions to be at high risk for celiac disease (CD) despite numerous reported associations between the two in adults and children. The objective of this study was to evaluate the prevalence of CD among patients presenting for pediatric rheumatology evaluation. METHODS: A total of 2125 patients presenting for initial evaluation by the Division of Pediatric Rheumatology at the Hospital for Special Surgery between June 2006 and December 2013 were screened for CD as a part of the standard initial serologic evaluation. The charts of these patients were evaluated retrospectively at the end of this period. RESULTS: 36 patients (30 girls, 6 boys, mean age 9.4 ± 4.3 years, range 2-16 years) received a diagnosis of CD after serologic testing and evaluation by pediatric gastroenterology. Eight additional patients with known diagnoses of CD presented during this time period. The total prevalence of CD over this 6.5-year period was 2.0%. The most common presenting complaints among patients diagnosed with CD were myalgias, arthralgias, and rash. Less frequently, patients reported gastrointestinal complaints including abdominal pain, nausea, and diarrhea. All patients reported improvement or complete resolution of their musculoskeletal symptoms after initiation of a gluten-free diet. CONCLUSIONS: This study identified 36 new cases of CD among children presenting for rheumatology evaluation, for an overall prevalence rate of 2.0%. The majority of patients who ultimately received a diagnosis of CD presented with extraintestinal manifestations. These results underscore the importance of screening children presenting for rheumatology evaluation for CD.